Examining the role of synaptic facilitation in cortical network function and behavioral flexibility - Project Summary This project seeks to unravel the crucial role of short-term plasticity (STP), specifically synaptic facilitation, in cognitive flexibility and the neural representations underlying it. STP, a significant modulator of neurotransmitter release, influences synaptic strength on short timescales, allowing for rapid, experience- dependent changes in neural circuit connectivity. Despite its proposed importance in cognitive functions and potential involvement in various neurological disorders such as schizophrenia, autism spectrum disorder, and Alzheimer's disease, the direct contribution of STP forms, like facilitation, to cognitive behaviors remains underexplored due to past methodological limitations. Our recent breakthroughs have identified key proteins responsible for STP, enabling the genetic manipulation of STP in vivo. Focusing on the protein synaptotagmin- 7 (SYT7), crucial for synaptic facilitation, we have found that mice lacking SYT7 (Syt7-/- mice) exhibit normal learning but impaired behavioral adaptation to changing reward conditions in a frontal cortex-dependent task. Preliminary in vivo electrophysiological evidence suggests altered prefrontal cortex activity in Syt7-/- mice during task learning, suggesting that SYT7-driven facilitation is integral to behavioral flexibility and relevant neural representations. To further explore this, this proposal is structured around three aims: 1) Characterize behavioral flexibility in Syt7-/- mice through cognitive operant assays to pinpoint the aspects of decision-making affected by facilitation deficits; 2) Examine frontal cortical activity in Syt7-/- mice during contingency changes in operant tasks, utilizing in vivo electrophysiology to identify how impaired facilitation impacts cortical representations of behaviorally relevant information; and 3) Model the impact of SYT7-driven synaptic facilitation in simulated neural networks, employing a multi-level modeling approach to delineate the role of synaptic facilitation in network dynamics and cognitive task learning flexibility. This comprehensive approach, combining behavioral assays, in vivo electrophysiology, and computational modeling, promises to offer unprecedented insights into the role of synaptic facilitation in cognitive flexibility and neural circuit function. By elucidating the mechanisms through which STP influences cognitive processes and their dysfunction in disease states, this project aims to lay the groundwork for novel therapeutic strategies targeting STP modulation. The expected outcomes have profound implications for our understanding of neural plasticity, cognitive function, and the treatment of cognitive impairments in neurological diseases, potentially revolutionizing approaches to enhancing cognitive resilience and flexibility.
